Camptothecin (CPT, 1, FIG. 1) is a naturally occurring alkaloid with remarkable antitumor effects.1-3 Its antitumor activity has been ascribed to its ability to interfere with the catalytic cycle of DNA Topoisomerase I (Topo I) by stabilizing an irreversible drug-enzyme-DNA ternary complex and preventing religation of single-strand DNA breaks induced by Topo I.4,5 Intensive synthetic medicinal chemistry efforts over the past decades have led to potent 1-derivatives, including is topotecan (2) and irinotecan (3), which are now used clinically to treat ovarian, small cell lung, and colon cancers. Also, several derivatives, such as gimatecan (4), CKD-602 (5), and BNP-1350 (6), are in various stages of preclinical or clinical development.6-8 Although clinically used 1-derivatives remain a promising class of antitumor agents, their therapeutic use has been severely hindered by toxicity issues and delivery problems, due to poor water solubility, as well as instability of the active lactone form, due to preferential binding of the opened carboxylate to serum albumin.9,10 
Several approaches, including the development of prodrugs (conjugates and polymer bound camptothecins), new formulations (liposomes or microparticulate carriers), and synthetic lipophilic camptothecins have been explored to improve the antitumor efficiency of the 1-family.11-13 Most of these strategies aim to maintain the active closed-lactone form in the plasma compailinent. A free 20-hydroxyl group favors lactone ring-opening due to formation of intra-molecular hydrogen bonding,14 while acylation of this group should stabilize the closed-lactone moiety.15 Moreover, steric bulk in the introduced ester moiety can be desirable to impede hydrolysis of the ester bond by various enzymes, including carboxylesterases, thereby reducing the toxicity. Indeed, our own results,16,17 as well as those of others with 20(S)—O-acyl esters,18,19 20(S)—O-carbonate linked tripeptide conjugates,20 and 20(S)—O-linked glycoconjugates,21 have supported the importance of esterified 1-derivatives for potent activity. Esterification of the 20-hydroxyl group also enhances plasma stability and augments in vivo antitumor activity compared with unmodified 1.
Amidines are well known as important pharmacophores22-25 and widely used in bioactive chemicals and drug molecular design. Also, the introduction of a sulfonyl group into a bioactive functional fragment results in significant changes in the compound's bioactivity;26,27 thus, sulfonylamidines may be useful structural motifs for optimization of bioactive molecules. Because this group is also quite bulky, it is likely to sterically prevent large enzymes from easily hydrolyzing a 20(S)—O-acyl ester of 1, which should also reduce the toxicity. In contrast, SN-38, the compound formed from the hydrolysis of 3, is quite toxic.28 Given these considerations, we postulated that the introduction of a sulfonylamidine group at the 20-position of 1 could lead to improved efficacy and reduced toxicity as well as optimize the physicochemical properties of a new 1-related anticancer drug candidate. Therefore, in the present study, we incorporated the functional fragment sulfonylamidine into 1 at the C-20 position via a Cu-catalyzed one pot reaction29 and synthesized a novel series of derivatives of 1 as potential antitumor agents.